Mechanism (s) of hypoxia-driven genetic instability. Hypoxia/anoxia signalling and subsequent adaptive biology is mediated by HIF1α transcription factors and altered protein through the unfolded protein response (UPR). These transcriptional and translational responses inhibit DNA repair by homologous recombination, non-homologous end-joining, and mismatch repair. The proteins downregulated by hypoxia are underlined. As a result, increased unrepaired double-strand breaks, replication errors and decreased centrosome function can accelerate genetic instability and lead to an aggressive, mutator phenotype.